INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
PREPULSID® 1 mg/mL

SCHEDULING STATUS:
Schedule 4.

PROPRIETARY NAME
(and dosage form):

PREPULSID^® 1 mg/mL
suspension.

COMPOSITION
Each mL contains 1,039 mg cisapride monohydrate equivalent to 1 mg cisapride anhydrous. Preservatives: methylparaben 0,18% m/v and propylparaben 0,02% m/v.

PHARMACOLOGICAL CLASSIFICATION
A. 11 Medicines acting on the gastrointestinal tract.

PHARMACOLOGICAL ACTION
IN ANIMALS
In isolated organs PREPULSID prevents gastric atony and enhances gastric peristaltic activity, antroduodenal co-ordination and small and large bowel motility. In dogs PREPULSID enhances digestive antroduodenal motility and co-ordination, accelerates gastric emptying, increases small bowel propulsive contractions and shortens intestinal transit time. Gastric secretion is not affected.
The mechanism of action of PREPULSID is mainly due to an enhancement of the physiological release of acetylcholine at the myenteric plexus level. PREPULSID does not induce muscarinic or nicotinic receptor stimulation, nor does it inhibit acetylcholinesterase activity. In vitro studies have shown that cisapride has serotonin (5-HT₄) receptor agonist activity in the colon.
IN MAN
GASTROINTESTINAL MOTILITY:
Oesophagus
PREPULSID increases oesophageal peristaltic activity and lower oesophageal sphincter tone. PREPULSID decreases oesophageal reflux of gastric contents and improves oesophageal clearance.
Stomach
PREPULSID increases gastric and duodenal contractility and antroduodenal co-ordination. PREPULSID decreases duodenogastric reflux. PREPULSID accelerates gastric and duodenal emptying.
Intestinal region
PREPULSID enhances intestinal propulsive activity and accelerates small and large bowel transit.
Other effects:
Due to its lack of direct cholinomimetic effects, PREPULSID does not increase basal and pentagastrin induced gastric acid secretion. Due to its relative lack of dopamine antagonistic properties PREPULSID very rarely affects prolactin plasma levels. The onset of pharmacological action of PREPULSID is approximately 30 to 60 minutes after oral administration.
After oral administration PREPULSID is rapidly and completely absorbed. Peak plasma levels are attained within 1 to 2 hours. The elimination half-life is 10 hours.
The main metabolic pathways of cisapride is through CYP3A4 (see "Interactions").
PREPULSID is extensively metabolized by oxidative N-dealkylation and aromatic hydroxylation. The excretion is almost exclusively metabolites and is about 50% of the dose in both urine and faeces. The excretion in maternal milk is very limited.
The absolute bioavailability of orally administered PREPULSID is around 40%. Plasma levels proportionally increase with oral doses from 5 to 20 mg.
Pharmacokinetics and steady state levels are unrelated to the duration of treatment. Cisapride is extensively bound to plasma proteins (97,5%).
Electrophysiological in vivo and in vitro studies have shown that cisapride under certain conditions may prolong cardiac repolarization. This may lead to prolongation of the QT-interval.

INDICATIONS
Infants and children:
In infants, chronic and excessive regurgitations or vomiting, when positional and dietary measurers have failed.
Intestinal pseudo-obstruction in children, associated with motility dysfunctions resulting in insufficient propulsive peristaltism and in stasis of gastric and intestinal contents.
Adults:
Gastroparesis, idiopathic or associated with diabetic neuropathy.
Symptoms of X-ray or endoscopy negative upper digestive discomfort characterised by early satiety, postprandial fullness, bloating, excessive belching, anorexia, vomiting or by ulcer-like complaints (epigastric burning or pain).
Gastro-oesophageal reflux disorders including oesophagitis and the maintenance thereof.

CONTRA-INDICATIONS
Known hypersensitivity to PREPULSID. Safety in pregnancy and lactation has not been established.
PREPULSID is contra-indicated in patients in whom an increase of gastro-intestinal motility could be harmful.
Use in prematurely born infants, (born at a gestational age of less than 36 weeks), from 0 through to 3 months after delivery date due to the risk of serious arrhythmias.
The concomitant oral or parenteral use of potent CYP3A4 inhibiting drugs including:

-	azole antifungals such as miconazole; fluconazole; itraconazole; econazole; ketoconazole; terconazole
-	macrolide antibiotics such as erythromycin, clarithromycin or troleandomycin;
-	HIV protease inhibitors such as ritonavir and indinavir;
-	Nefazodone.

Cisapride is contra-indicated in patients with the following risk factors for cardiac arrhythmia: patients with a known congenital long QT-interval; an acquired long QT-interval; or a family history of QT interval prolongation (such as congenital long QT syndrome, idiopathic QT interval prolongation, QT interval prolongation associated with diabetes mellitus), with a previous history of ventricular arrhythmia or torsades de pointes, known hypokalaemia or hypomagnesaemia, clinically significant bradycardia or when used in combination with medicines known to prolong the QT interval such as certain antimalarials, antiarrhythmics, certain antihistamines, tricyclic antidepressants and certain antipsychotic medicines (see section “Interactions”).

WARNINGS

Patients with, or suspected of having, the following risk factors for cardiac arrhythmia should be carefully evaluated prior to administration of cisapride: a history of, significant cardiac disease (including serious ventricular arrhythmia, second or third degree atrioventricular block, sinus node dysfunction, congestive heart failure, ischemic heart disease), family history of sudden death, renal failure (particularly when on chronic dialysis) significant chronic obstructive pulmonary disease and respiratory failure, risk factors for electrolyte disturbances as seen in patients taking potassium-wasting diuretics in association with the administration of insulin in acute settings or in patients with persistent vomiting and/or diarrhoea. In these patients and ECG to exclude a prolonged QT-interval an assessment of serum electrolytes (potassium and magnesium) and renal function should be performed as part of this evaluation. Benefits should be weighed against potential risks and cisapride should only be used under appropriate medical supervision. For patients with a QTc of >450 msec or with uncorrected electrolyte disturbances cisapride should, not be used (see “CONTRA-INDICATIONS”)

DOSAGE AND DIRECTIONS FOR USE
INFANTS AND CHILDREN UP TO 25 kg (0,2 mg suspension/kg bodyweight): 1 intake (0,2 mg/kg) not more than three to four times daily. The drinkable suspension is the best form to use. Intakes are indicated on the dosing pipette as a function of body weight.
CHILDREN BETWEEN 25 AND 50 kg: A maximum of 5 mg four times a day. Either the PREPULSID tablets or the oral suspension can be used. One (1) full pipette of oral suspension, as provided with the bottle, contains 5 mg.
Directions for use of the pipette in children:
NOTE: The pipette must not be used for administration of any other medicine. The pipette is specifically calibrated for administration of PREPULSID 1 mg/mL. Shake before use.

Fig 1:	The bottle comes with a child-proof cap, and should be opened as follows: {illustrated} –        push the plastic screw cap down while turning it counter clockwise. –        Remove the unscrewed cap.
Fig 2:	Pull the pipette out of its case and insert it into the bottle.
Fig 3:	While holding down the bottom ring, pull the top ring up to the mark corresponding to the child's weight in kilograms.
Fig 4:	Holding the bottom ring, remove the entire pipette from the bottle.

Empty the pipette and fit it back into its case. Close the bottle.
ADULTS: Depending on the severity of the condition: 5 to 10 mg (5 to 10 mL) PREPULSID two to four times daily.
Oesophagitis: 20 mg (20 mL) PREPULSID twice daily (before breakfast and before retiring) or alternatively, 10 mg (10 mL) PREPULSID three to four times a day before meals and before retiring.
Maintenance treatment of oesophagitis: 20 mg (20 mL) PREPULSID once daily (before retiring) or alternatively 10 mg (10 mL) PREPULSID twice a day (before breakfast and on retiring). In patients with very severe disease, it may be necessary to double the dose to a maximum of 20 mg (20 mL) twice daily.
The maximum recommended dose should not be exceeded.
In the treatment of upper digestive disorders, PREPULSID is given at least 15 minutes before a meal together with some beverage except for grapefruit juice. Normally PREPULSID is given three times daily but in severe conditions and particulary in the treatment of oesophagitis, one more intake before retiring may be warranted.
In hepatic and renal insufficiency, it is recommended to halve the daily dose.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Abdominal cramps, borborygmi and diarrhoea may occur. Should severe abdominal cramps occur with 20 mg per intake, it is recommended to halve the dose per intake.
Cases of hypersensitivity including rash, pruritis and urticaria, bronchospasm, headache or lightheadedness and dose related increase in urinary frequency have been reported less frequently.
Cases of cardiac arrhythmia, including ventricular tachycardia, ventricular fibrillation, torsade de pointes, and QT-prolongation have been reported. Some patients did not have known cardiac histories. Most of these patients had been receiving multiple other medications including CYP3A4 inhibiting drugs and/or had pre-existing cardiac disease or risk factors for arrhythmias (see "Interactions" and "Warnings").
Exceptional cases of reversible liver function abnormalities, with or without cholestasis, have been reported.
Hyperprolactinaemia which may cause gynaecomastia and galactorrhoea has also been reported. All of these events were reversible on discontinuation of treatment.
There are isolated reports of central nervous system effects i.e. convulsive seizures and extrapyramidal effects.
Driving and machine operating ability: PREPULSID does not affect psychomotor function and does not induce sedation or drowsiness. PREPULSID may however accelerate the absorption of central nervous system depressants and alcohol. Caution should therefore be exercised when PREPULSID is administered with these drugs.
In hepatic and renal insufficiency, it is recommended to halve the daily dose.
In the elderly, steady state plasma levels are generally higher due to a moderate prolongation of the elimination half-life. Therapeutic doses, however, are similar to those used in younger patients.
Interactions:
The acceleration by PREPULSID of gastric emptying may affect the rate of absorption of drugs: absorption of drugs from the stomach may be diminished, whereas absorption of drugs from the small bowel may be accelerated (e.g. benzodiazepines, anticoagulants, paracetamol H₂-blockers).
In patients receiving anticoagulants, the coagulation time may increase. It is advisable to check the coagulation time within the first few days after start and discontinuation of PREPULSID treatment to adapt the anticoagulant dose if necessary.
In the case of drugs that require individual titration, it may be useful to monitor plasma levels of such drugs when PREPULSID is associated.
The sedative effects of central nervous system depressants and of alcohol may be accelerated.
The effects of PREPULSID on gastrointestinal motility are for the most part antagonised by anticholinergic drugs.
The main metabolic pathway of cisapride is through CYP3A4. The concomitant oral or parenteral use of drugs that significantly inhibit these enzymes may result in increased plasma levels of cisapride. and could increase the risk of QT-prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, torsades de pointes.. Therefore the use of such drugs is contra-indicated. Examples include the following:

-	azole antifungals such as miconazole; fluconazole; itraconazole; econazole; ketoconazole terconazole
-	macrolide antibiotics such as erythromycin, clarithromycin or troleandomycin;
-	HIV protease inhibitors, such as ritonavir and indinavir;
-	nefazodone.

Drugs known to prolong the QT-interval are also contra-indicated. Examples include certain antiarrhythmics, such as those of Class IA (such as quinidine, disopyramide and procainamide) and Class III (such as bretylium, amiodarone and sotalol); tricyclic antidepressants (such as amitriptyline); certain tetracyclic antidepressants (such as maprotiline); certain antipsychotic medications (such as, thioridazine, chlorpromazine, haloperidol, lithium, pimozide and sertindole) certain antihistamine (such as astemizole and terfenadine); certain anti-malarials (such as quinine, halofantrine and mefloquine); pentamidine, bepridil and sparfloxacin.
Co-administration of grapefruit juice with cisapride increases the bioavailability of cisapride and concomitant use should be avoided.
Cimetidine causes a slight increase in PREPULSID plasma levels which is not considered to be clinically significant.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Symptoms
The symptoms that occur most frequently after overdosing are abdominal cramping and increased stool frequency. Cases of QT-prolongation and ventricular arrhythmia have been reported.
In infants (< 1 year of age), mild sedation, apathy and atony were observed.
Treatment
In case of overdosage, the administration of activated charcoal and close observation of the patient are recommended.
It is recommended that patients be evaluated for possible QT-prolongation and for factors that can predispose to the occurrence of torsade de pointes, such as electrolyte disturbances (especially hypokalaemia or hypomagnesaemia) and bradycardia.

IDENTIFICATION
White suspension.

PRESENTATION
100 mL glass bottle with graduated pipette.

STORAGE INSTRUCTIONS
Store below 25°C. Protect from light.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER
V/11/145

NAME AND BUSINESS ADDRESS OF THE APPLICANT
JANSSEN –CILAG
JANSSEN PHARMACEUTICA (PTY) LTD
(Reg. No. 80/11122/07)
15th ROAD
HALFWAY HOUSE 1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT
23 July 1999

©JPh (Pty) Ltd 1991
                Code: 023832
                        2000A
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